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Synthetic Forms Most Beautiful: Engineering Insights into Self-Organization

Physiology (Bethesda, Md.) 2025年第4期40卷 0-0页

作者： Xu, Zhejing Chang, Chih-Chia Coyle, Scott M. Department of Biochemistry University of Wisconsin-Madison WI United States Integrated Program in Biochemistry Graduate Program University of Wisconsin-Madison WI United States Biophysics Graduate Program University of Wisconsin-Madison WI United States

Reflecting on the diversity of the natural world, Darwin famously observed that "from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved." However, the examples that we are able to observe in nature are a consequence of chance, constrained by selection, drift, and epistasis. Here we explore how the efforts of synthetic biology to build new living systems can expand our understanding of the fundamental design principles that allow life to self-organize biological form, from cellular to organismal levels. We suggest that the ability to impose a length or timescale onto a biological activity is an essential strategy for self-organization in evolved systems and a key design target that is now being realized synthetically at all scales. By learning to integrate these strategies together, we are poised to expand on evolution's success and realize a space of synthetic forms not only beautiful but with diverse applications and transformative potential.

关键词： biological form and function evolution self-organization spatiotemporal control synthetic biology

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O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine (vol 13, 2904, 2022)

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NATURE COMMUNICATIONS 2022年第1期13卷 2904页

作者： Kim, Kibum Yoo, Hee Chan Kim, Byung Gyu Kim, Sulhee Sung, Yulseung Yoon, Ina Yu, Ya Chun Park, Seung Joon Kim, Jong Hyun Myung, Kyungjae Hwang, Kwang Yeon Kim, Sunghoon Han, Jung Min Interdisciplinary Program of Integrated OMICS for Biomedical Science Graduate School Yonsei University Seoul 03722 South Korea. Yonsei Institute of Pharmaceutical Sciences College of Pharmacy Yonsei University Incheon 21983 South Korea. Center for Genomic Integrity Institute for Basic Science Ulsan 44919 South Korea. Department of Biotechnology College of Life Sciences and Biotechnology Korea University Seoul 02841 South Korea. Department of Biochemistry School of Medicine Catholic University of Daegu Daegu 42472 South Korea. Interdisciplinary Program of Integrated OMICS for Biomedical Science Graduate School Yonsei University Seoul 03722 South Korea. jhan74@yonsei.ac.kr.

All living organisms have the ability to sense nutrient levels to coordinate cellular metabolism. Despite the importance of nutrient-sensing pathways that detect the levels of amino acids and glucose, how the availability of these two types of nutrients is integrated is unclear. Here, we show that glucose availability regulates the central nutrient effector mTORC1 through intracellular leucine sensor leucyl-tRNA synthetase 1 (LARS1). Glucose starvation results in O-GlcNAcylation of LARS1 on residue S1042. This modification inhibits the interaction of LARS1 with RagD GTPase and reduces the affinity of LARS1 for leucine by promoting phosphorylation of its leucine-binding site by the autophagy-activating kinase ULK1, decreasing mTORC1 activity. The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. This work demonstrates that LARS1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.

关键词： Glycobiology Metabolism Nutrient signalling Post-translational modifications

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Synthesis and Evaluation of Quinolino-Benzoxaboroles as Potential Antimicrobial Agents

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International Journal of Organic Chemistry 2022年第2期12卷 53-63页

作者： Greeshma P. Kumpati Michael J. Williams Srinidhi Mereddy Joseph L. Johnson Shirisha Jonnalagadda Integrated Biosciences Graduate Program University of Minnesota Duluth MN USA Department of Chemistry and Biochemistry University of Minnesota Duluth Duluth MN USA Department of Biology University of Washington Seattle WA USA

Several quinolino-benzoxaborole derivatives have been prepared to start from aminobenzoxaboroles. These derivatives have been evaluated for their anti-cancer activity on human and murine cancer cell lines and based on their relative non-toxicity, these compounds were further evaluated for their antibacterial activity against E. coli, B. subtilis, and M. smegmatis. The synthesized compounds were also evaluated for antifungal activity in C. albicans and C. neoformans.

关键词： Benzoxaboroles Aminobenzoxaboroles Quinolino-Benzoxaboroles Anti-Microbial Agents

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Another wrinkle with age: Aged collagen and intra-peritoneal metastasis of ovarian cancer

Aging and Cancer

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Aging and Cancer 2022年第2期3卷 116-129页

作者： Harper, Elizabeth I. Hilliard, Tyvette S. Sheedy, Emma F. Carey, Preston Wilkinson, Paul Siroky, Michael D. Yang, Jing Agadi, Elizabeth Leonard, Annemarie K. Low, Ethan Liu, Yueying Biragyn, Arya Annunziata, Christina M. Stack, Mary Sharon Department of Chemistry and Biochemistry University of Notre Dame Notre Dame IN United States Harper Cancer Research Institute University of Notre Dame Notre Dame IN United States Integrated Biomedical Sciences Graduate Program University of Notre Dame Notre Dame IN United States National Institute on Aging Bethesda MD United States National Cancer Institute Bethesda MD United States

Background: Age is the most significant risk factor for ovarian cancer (OvCa), the deadliest gynecologic malignancy. Metastasizing OvCa cells adhere to the omentum, a peritoneal structure rich in collagen, adipocytes, and immune cells. Ultrastructural changes in the omentum and the omental collagen matrix with aging have not been evaluated. Aim: The aim of this study was to test the hypothesis that age-related changes in collagen in the ovarian tumor microenvironment promote OvCa metastatic success in the aged host. Methods/Results: Young (3–6 months) and aged mice (20–23 months) were used to study the role of aging in metastatic success. Intra-peritoneal (IP) injection of ID8Trp53^–/– OvCa cells showed enhanced IP dissemination in aged versus young mice. In vitro assays using purified collagen demonstrated reduced collagenolysis of aged fibers, as visualized using scanning electron microscopy (SEM) and quantified with a hydroxyproline release assay. Omental tumors in young and aged mice showed similar collagen deposition;however enhanced intra-tumoral collagen remodeling was seen in aged mice probed with a biotinylated collagen hybridizing peptide (CHP). In contrast, second harmonic generation (SHG) microscopy showed significant differences in collagen fiber structure and organization in omental tissue, and SEM demonstrated enhanced omental fenestration in aged omenta. Combined SHG and Alexa Fluor-CHP microscopy in vivo demonstrated that peri-tumoral collagen was remodeled more extensively in young mice. This collagen population represents truly aged host collagen, in contrast to intra-tumoral collagen that is newly synthesized, likely by cancer-associated fibroblasts. Conclusions: Our results demonstrate that tumors in an aged host can grow with minimal collagen remodeling, while tumors in the young host must remodel peri-tumoral collagen to enable effective proliferation, providing a mechanism whereby age-induced ultrastructural changes in collagen and

关键词： aging collagen metastasis omentum ovarian cancer

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Optimization of surface plasmon resonance based assay for investigating T-antigen helicase activity

Journal of Biotech Research

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Journal of Biotech Research 2010年第1期2卷 56-66页

作者： Plyler, Jason R. Sanjar, Fatemeh Howard, Rhonda Araki, Naoko David, Wendi M. Department of Chemistry and Biochemistry Texas State University-San Marcos 601 University Drive San Marcos TX 78666 United States Integrated Multidisciplinary Graduate Program UT Health Science Center San Antonio TX 78229 United States

Due to the increasing number of helicases shown to unwind quadruplex DNA structures in addition to duplex DNA, the biological significance of this activity is currently under investigation. One limitation of traditional gel analysis of helicase activity is the inability to effectively monitor unwinding of intramolecular G-quadruplex DNA substrates. Optimization of our novel SPR-based assay for monitoring the helicase activity of simian virus 40 (SV40) large T-antigen (T-ag) was undertaken to explore limitations and improvements in the ability to investigate G-quadruplex helicase activity. Although T-ag helicase was used, the assay is general in nature. An improved method for assessing unwinding of intramolecular G-quadruplex DNA substrates was developed.

关键词： Antigens

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Practical axial optical trapping

Practical axial optical trapping

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作者： MacK, A.H. Schlingman, D.J. Regan, L. Mochrie, S.G.J. Integrated Graduate Program in Physical and Engineering Biology Yale University New Haven CT 06511 United States Department of Applied Physics Yale University New Haven CT 06511 United States Department of Molecular Biophysics and Biochemistry Yale University New Haven CT 06511 United States Department of Chemistry Yale University New Haven CT 06511 United States Department of Physics Yale University New Haven CT 06511 United States

We describe a new method for calibrating optical trapping measurements in which tension is applied in the direction of the laser beam to a molecule tethered between a surface and an optically trapped bead. Specifically, we present a generally-applicable procedure for converting from the measured scattering intensity and the measured stage displacement to applied tension and bead-coverslip separation, using measurements of the light intensity scattered from an untethered, trapped bead. Our calibration accounts for a number of effects, including aberrations and the interference of forward-reflected bead-scattered light with the trapping beam. To demonstrate the accuracy of our method, we show measurements of the DNA force-versus-extension relation using a range of laser intensities, and show that these measurements match the expected extensible wormlike-chain (WLC) behavior. Finally, we also demonstrate a force-clamp, in which the tension in a tether is held fixed while the extension varies as a result of molecular events. © 2012 American Institute of Physics.

关键词： Equipment

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Functional annotation of chemical libraries across diverse biological processes (vol 13, pg 982, 2017)

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NATURE CHEMICAL BIOLOGY 2017年第12期13卷 1286-1286页

作者： Piotrowski, Jeff S. Li, Sheena C. Deshpande, Raamesh Simpkins, Scott W. Nelson, Justin Yashiroda, Yoko Barber, Jacqueline M. Safizadeh, Hamid Wilson, Erin Okada, Hiroki Gebre, Abraham A. Kubo, Karen Torres, Nikko P. LeBlanc, Marissa A. Andrusiak, Kerry Okamoto, Reika Yoshimura, Mami DeRango-Adem, Eva van Leeuwen, Jolanda Shirahige, Katsuhiko Baryshnikova, Anastasia Brown, Grant W. Hirano, Hiroyuki Costanzo, Michael Andrews, Brenda Ohya, Yoshikazu Osada, Hiroyuki Yoshida, Minoru Myers, Chad L. Boone, Charles RIKEN Center for Sustainable Resource Science Wako Saitama Japan Department of Computer Science and Engineering University of Minnesota-Twin Cities Minneapolis Minnesota USA Bioinformatics and Computational Biology Program University of Minnesota-Twin Cities Minneapolis Minnesota USA Department of Electrical and Computer Engineering University of Minnesota-Twin Cities Minneapolis Minnesota USA Department of Integrated Biosciences Graduate School of Frontier Sciences University of Tokyo Kashiwa Chiba Japan Donnelly Centre University of Toronto Toronto Ontario Canada Institute of Molecular and Cellular Biosciences Center for Epigenetic Disease University of Tokyo Bunkyo-ku Tokyo Japan Lewis-Sigler Institute for Integrative Genomics Princeton University Princeton New Jersey USA Department of Biochemistry University of Toronto Toronto Ontario Canada.

Chemical-genetic approaches offer the potential for unbiased functional annotation of chemical libraries. Mutations can alter the response of cells in the presence of a compound, revealing chemical-genetic interactions that can elucidate a compound’s mode of action. We developed a highly parallel, unbiased yeast chemical-genetic screening system involving three key components. First, in a drug-sensitive genetic background, we constructed an optimized diagnostic mutant collection that is predictive for all major yeast biological processes. Second, we implemented a multiplexed (768-plex) barcode-sequencing protocol, enabling the assembly of thousands of chemical-genetic profiles. Finally, based on comparison of the chemical-genetic profiles with a compendium of genome-wide genetic interaction profiles, we predicted compound functionality. Applying this high-throughput approach, we screened seven different compound libraries and annotated their functional diversity. We further validated biological process predictions, prioritized a diverse set of compounds, and identified compounds that appear to have dual modes of action.

关键词： Chemical genetics High-throughput screening Networks and systems biology Target identification

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Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN

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Nature Biotechnology 2010年第3期28卷 271-274页

作者： Foust, Kevin D. Wang, Xueyong McGovern, Vicki L. Braun, Lyndsey Bevan, Adam K. Haidet, Amanda M. Le, Thanh T. Morales, Pablo R. Rich, Mark M. Burghes, Arthur H. M. Kaspar, Brian K. Center for Gene Therapy Research Institute at Nationwide Children's Hospital Columbus OH United States Wright State University Dayton OH United States Department of Molecular and Cellular Biochemistry United States Integrated Biomedical Graduate Program Ohio State University Columbus OH United States Mannheimer Foundation Inc. Homestead FL United States

Spinal muscular atrophy (SMA), the most common autosomal recessive neurodegenerative disease affecting children, results in impaired motor neuron function. Despite knowledge of the pathogenic role of decreased survival motor neuron (SMN) protein levels, efforts to increase SMN have not resulted in a treatment for patients. We recently demonstrated that self-complementary adeno-associated virus 9 (scAAV9) can infect ∼60% of motor neurons when injected intravenously into neonatal mice. Here we use scAAV9-mediated postnatal day 1 vascular gene delivery to replace SMN in SMA pups and rescue motor function, neuromuscular physiology and life span. Treatment on postnatal day 5 results in partial correction, whereas postnatal day 10 treatment has little effect, suggesting a developmental period in which scAAV9 therapy has maximal benefit. Notably, we also show extensive scAAV9-mediated motor neuron transduction after injection into a newborn cynomolgus macaque. This demonstration that scAAV9 traverses the blood-brain barrier in a nonhuman primate emphasizes the clinical potential of scAAV9 gene therapy for SMA. © 2010 Nature America, Inc. All rights reserved.

关键词： Gene therapy

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Unwinding and rewinding the nucleosome inner turn: Force dependence of the kinetic rate constants

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Physical Review E 2013年第1期87卷 012710-012710页

作者： S. G. J. Mochrie A. H. Mack D. J. Schlingman R. Collins M. Kamenetska L. Regan Integrated Graduate Program in Physical and Engineering Biology Yale University New Haven Connecticut 06520 USA Department of Applied Physics Yale University New Haven Connecticut 06520 USA Department of Physics Yale University New Haven Connecticut 06520 USA Department of Molecular Biophysics and Biochemistry Yale University New Haven Connecticut 06520 USA Department of Chemistry Yale University New Haven Connecticut 06520 USA

A simple model for the force-dependent unwinding and rewinding rates of the nucleosome inner turn is constructed and quantitatively compared to the results of recent measurements [A. H. Mack et al., J. Mol. Biol. 423, 687 (2012)]. First, a coarse-grained model for the histone-DNA free-energy landscape that incorporates both an elastic free-energy barrier and specific histone-DNA bonds is developed. Next, a theoretical expression for the rate of transitions across a piecewise linear free-energy landscape with multiple minima and maxima is presented. Then, the model free-energy landscape, approximated as a piecewise linear function, and the theoretical expression for the transition rates are combined to construct a model for the force-dependent unwinding and rewinding rates of the nucleosome inner turn. Least-mean-squares fitting of the model rates to the rates observed in recent experiments rates demonstrates that this model is able to well describe the force-dependent unwinding and rewinding rates of the nucleosome inner turn, observed in the recent experiments, except at the highest forces studied, where an additional ad hoc term is required to describe the data, which may be interpreted as an indication of an alternate high-force nucleosome disassembly pathway, that bypasses simple unwinding. The good agreement between the measurements and the model at lower forces demonstrates that both specific histone-DNA contacts and an elastic free-energy barrier play essential roles for nucleosome winding and unwinding, and quantifies their relative contributions.

关键词： CHROMATIN HISTONES LEAST squares CHEMICAL bonds ANALYSIS of DNA

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Void distributions reveal structural link between jammed packings and protein cores

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Physical Review E 2019年第2期99卷 022416-022416页

作者： John D. Treado Zhe Mei Lynne Regan Corey S. O'Hern Department of Mechanical Engineering & Materials Science Yale University New Haven Connecticut 06520 USA Integrated Graduate Program in Physical & Engineering Biology Yale University New Haven Connecticut 06520 USA Department of Chemistry Yale University New Haven Connecticut 06520 USA Department of Molecular Biophysics & Biochemistry Yale University New Haven Connecticut 06520 USA Department of Physics Yale University New Haven Connecticut 06520 USA Department of Applied Physics Yale University New Haven Connecticut 06520 USA Program in Computational Biology and Bioinformatics Yale University New Haven Connecticut 06520 USA

Dense packing of hydrophobic residues in the cores of globular proteins determines their stability. Recently, we have shown that protein cores possess packing fraction ϕ≈0.56, which is the same as dense, random packing of amino-acid-shaped particles. In this article, we compare the structural properties of protein cores and jammed packings of amino-acid-shaped particles in much greater depth by measuring their local and connected void regions. We find that the distributions of surface Voronoi cell volumes and local porosities obey similar statistics in both systems. We also measure the probability that accessible, connected void regions percolate as a function of the size of a spherical probe particle and show that both systems possess the same critical probe size. We measure the critical exponent τ that characterizes the size distribution of connected void clusters at the onset of percolation. We find that the cluster size statistics are similar for void percolation in packings of amino-acid-shaped particles and randomly placed spheres, but different from that for void percolation in jammed sphere packings. We propose that the connected void regions are a defining structural feature of proteins and can be used to differentiate experimentally observed proteins from decoy structures that are generated using computational protein design software. This work emphasizes that jammed packings of amino-acid-shaped particles can serve as structural and mechanical analogs of protein cores, and could therefore be useful in modeling the response of protein cores to cavity-expanding and -reducing mutations.

关键词： Jamming Protein structure Packing & jamming problems Proteins Crystal structures Finite-size scaling Molecular dynamics Percolation theory

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